The sensation of smell enables us to gain valuable information about a plethora of chemicals in our immediate environment, and to respond appropriately. Olfactory receptor neurons (ORNs) are responsible for detection of these chemicals and are unique among neurons because following death due to cytotoxic insults or viral infections, they are replaced by new ORNs. This process occurs in the olfactory epithelium (OE) lining the nose and involves the step-wise transformation of mitotic basal ("stem") cells into differentiated mature ORNs. In experiments outlined in this application, we will investigate the role of pituitary adenylate cyclase activating peptide (PACAP) in proliferation and maturation of normal developing and regenerating OE. PACAP is an intraepithelial peptide that acts as a cue for the regeneration of ORNs and for initiating defensive responses within ORNs to minimize cell death or apoptosis. The interaction of the signaling pathways activated by cell-extrinsic PACAP and cell-intrinsic electrical activity of ORNs in promoting differentiation of progenitor cells into differentiated ORNs will be investigated. In three specific aims, we will determine: (1) the expression profiles of PACAP and isoforms of its receptor (PAC1) in the developing and adult OE of wild-type and PACAP ko mice with and without bulb ablation; (2) the contributions of PACAP and cell-intrinsic activity in driving the maturation of ORNs and proliferation of basal stem cells, and (3) how PACAP prevents apoptosis of ORNs following cytokine inundation of the OE and injury caused by bulb ablation. Our studies are timely and critical for gaining an understanding of the cellular and signaling mechanisms involved in neuroregeneration in general, and are directly relevant to addressing the causes and potentials remedies of neurodegenerative diseases such as Alzheimer's and Parkinson's disease in which olfactory dysfunction is an early symptom.